The gene encoding the HER2/neu/ErbB2 receptor tyrosine kinase is one of a small number of gene known to be altered in human breast carcinoma, and is a validated therapeutic target. We hypothesize that optima development and DEPLOYMENT of such therapeutics requires a thorough understanding of the normal biological function of ErbB2, including its normal functions in the mammary gland, and its regulation by interactions with other ErbB family receptors. Aim continues our ongoing work on basic signaling principles governing EGF family receptors Aims 2 and 3 are geared towards determining the normal function of the ErbB family receptors in normal mammary development. Aim 1. Work in the preceding grant cycle revealed that the positioning of ErbB2 extracellular domains influence the strength or quality of the efferent signal. Comparison of transcription profiles for EGFR activated by different EGF agonists will be used to determine if this mechanism is used to generate signaling diversity among the agonists. Aim 2. Transplantation techniques will be used to determine consequences of ErbB2 and ErbB3 gene disruption on mammary development, and whether limiting functions are performed in the stroma or epithelium. Aim 3.Transplantation techniques will be used to determine consequences of disruption of sets of ErbB family receptors on mammary development. This work has direct relevance to breast cancer and a number of other carcinomas that overexpress HER2/neu, since the receptor is now a validated therapeutic target.